Healthcare facilities are known to be a breeding ground for a variety of infectious diseases. The pathogens that cause these diseases can reside in many places in the hospital environment—not just in devices and equipment used in medical procedures, but also from common surfaces such as floors, telephones, bed rails, bathroom fixtures, hand rails, and computer keyboards. Microbes living on these contaminated surfaces are touched by multiple people leading to increased spread of hospital acquired infections (HAIs), and it has been estimated that 1 in 20 hospital patients will be infected with an HAI as a direct result of the care they receive at hospital.
Hydrogen peroxide (HP) is currently receiving renewed attention as a safe, environmentally-friendly, and cost-effective antimicrobial, as evidenced by the recent introduction of several commercially-available cleaning products based on HP.
Casual contact with everyday objects is a leading cause for the spread of infection, and disease. One dirty hand can infect multiple surfaces. Rubbing one's eye or eating a sandwich then becomes a vector for infection. Even surfaces are cleaned and sanitized frequently can quickly become recontaminated after the applied disinfectant has evaporated.
Antimicrobial cleaning products based on hydrogen peroxide have recently been commercialized for hospital and home use by several leading brands, including Clorox and Lysol. Unfortunately, since HP is volatile, surfaces cleaned with these products (or even with alcohol, bleach, etc.) lose the antimicrobial effect immediately after drying.
Hospitals, nursing homes, and other healthcare facilities are known to be a breeding ground for a variety of infectious diseases. The pathogens that cause these diseases can reside in many places in the hospital environment including floors, curtains, telephones, bedding, bed rails, chairs and chair backs, hand rails, and computer keyboards. In a surface contamination targeting study conducted in a Welsh hospital, 2,573 touch actions were examined The results showed that 1,489 touch actions were by nurses, 519 were by patients, 380 were by visitors, and 185 were by physicians (Obee, Peter; PhD Thesis: “Hospital Surfaces and their Importance in Cross Contamination and the Spread and Transmission of Bacteria”, Accessed: University of Wales, Institute Cardiff Repository URI: <http://hdl.handle.net/10369/844>). This demonstrates the high potential for spreading of microbes from one group to the other. In an extensive contamination study based in a southern Ontario hospital, 11.8% of surfaces sampled were positive for MRSA (n=612) while 2.4 (n=552) of surfaces were positive for C. difficile (Faires, Meredith C.; Pearl, David L.; Ciccotelli, William A.; Straus, Karen; Zinken, Giovanna; Berke, Olaf; Reid-Smith, Richard J.; and Weese, J. Scott; “A Prospective Study to Examine the Epidemiology of Methicillin-Resistant Staphylococcus aureus and Clostridium difficile Contamination in the General Environment of Three Community Hospitals in Southern Ontario, Canada”, BMC Infectious Diseases 12(290), (2012). Furthermore, a study from as far back as 1997 discovered that 42% of medical personnel who had no direct contact with actual infected patients, had MRSA contaminated gloves acquired directly from hospital room surfaces (Boyce, John M.; Potter-Bynoe, Gail; Chenevert, Claire; and King, Thomas; “Environmental Contamination Due to Methicillin-Resistant Staphylococcus aureus: Possible Infection Control Implications”, Infection Control and Hospital Epidemiology 18(9), p 622-627, (1997). Other studies indicated that certain Gram-positive species such as Staph. aureus can survive up to 7 months on dry surfaces, while certain Gram-negative organisms such as E. coli and Pseudomonas aeruginosa can last up to 16 months on dry surfaces (Kramer, Axel; Schwebke, Ingeborg; and Kampf, Günter: “How Long Do Nosocomial Pathogens Persist on inanimate Surfaces? A Systematic Review”, BMC Infectious Diseases 6(1), p 130, (2006).
Contaminated surfaces such as these are leading to increased incidences of hospital acquired infections (HAIs) and it has been estimated that 1 in 20 hospital patients will be infected with an HAI as a direct result of the care they receive at hospital institutions (Scott II, R. Douglas; “The Direct Costs of Healthcare-Associated Infections in U.S. Hospitals and the Benefits of Prevention”, Division of Healthcare Quality Promotion: National Center for Preparedness, Detection, and Control of Infectious Diseases, Centers for Disease Control and Prevention, (2009). One study estimates that 1.7 million HAIs occurred in U.S. hospitals in 2002, leading to approximately 99,000 deaths, exceeding the number of cases of any currently notifiable disease, and also exceeding the number attributable to several of the top ten leading causes of death reported in U.S. vital statistics (Klevens, R. Monina; Edwards, Johnathan R.; Richards Jr., Chesley L.; Horan, Teresa C.; Gaynes, Robert P.; Pollock, Daniel A.; Cardo, Denise M.; “Estimating Health Care-Associated Infections and Deaths in U.S. Hospitals, 2002”, Public Health Reports 1 22(2), p 160-166, (2007). Not only are these increased numbers of infections contributing to the decline of the health of U.S. citizens; the direct costs of these HAIs to hospitals are estimated to be between $28.4 and $45 billion per year in the U.S. (Scott 2009). These increased costs result from longer hospitalizations, increased use of diagnostic imaging, increased use of intensive care, and increased use of newer more expensive antibiotics. Assuming a 20%-70% HAI prevention range, preventing HAIs can have cost benefits from $5.7 billion to $31.5 billion.
Further compounding the issue, new legislation and national government programs are making serious adjustments in response to the increase of HAIs. In 2008, the United States Centers for Medicare and Medicaid Services halted reimbursements to hospitals for certain “reasonably preventable” HAIs as a result of the 2005 Deficit Reduction Act (Graves, Nicholas; and McGowan, John E.; “Nosocomial Infection, the Deficit Reduction Act, and Incentives for Hospitals”, JAMA: The Journal of the American Medical Association, 300(13) p 1577-1579, (2008). Starting Jul. 1, 2012, states were required to implement non-payment polices for healthcare-associated conditions and public reporting of these infections is now mandatory. Additionally, as of Oct. 1, 2012, hospitals with HAI-associated readmission rates surpassing the predicted level will be punished with a 1% decrease of all Medicare payments and the penalty will rise to 3% by 2015 (UMF Corporation, “Doing Everything: Multimodal Intervention to Prevent Healthcare-Associated Infections”, White Paper: UMF Corporation, (2012).
Hydrogen peroxide is a favored antimicrobial in many applications because its breakdown products, water and oxygen, are innocuous, and it tends to have broad spectrum antimicrobial activity, meaning that it is not only effective against bacteria, but it also kills viral and fungal organisms. Broad spectrum activity is important in situations where harmful organisms are present but their identity is not known. Hydrogen peroxide is a well-known antiseptic which has been extensively employed in aqueous solution for the treatment of infectious processes in both human and veterinary topical therapy. Both HP and zinc oxide (ZnO) have received GRAS (Generally Recognized as Safe) designations from the U.S. Food and Drug Administration (FDA). Both are also widely-available and relatively-inexpensive commodity materials.
The designation of compounds, formulations and devices as “antimicrobial” is often misused. To a layman, a 90% reduction of bacteria on a surface may seem great; however, one must remember that bacteria multiply exponentially and quickly. For instance, it is said that a single E. coli (EC) cell under favorable conditions can multiply into over ten million cells within 12 hours! Thus, it is imperative that a useful antimicrobial product give an extremely high level of microbial kill. For this reason, the efficacy of antimicrobial products is commonly described in terms of “log reduction.” This means that a 90% kill equals 1-log reduction, and 99% kill equals a 2-log reduction. Killing 99.9999% of the bacteria equals a 6-log reduction. Regulatory agencies such as the FDA and U.S. Environmental Protection Agency (EPA) historically have required a minimum of 3-log performance for a product to be classified as “antimicrobial”; however, today a 4-log to 6-log requirement is becoming more common. For this reason, testing of bactericidal activity is commonly done using challenge levels of at least 106 cfu/mL (colony forming units per milliliter).
Zinc oxide (ZnO) has received much attention in recent years as an antimicrobial agent. It has been found that ZnO nanoparticles show a higher efficacy than conventional ZnO powders in the micron size range. This is to be expected, based on the higher surface area of the nanoparticles. Indeed, high antimicrobial efficacy is realized for ZnO nanoparticles in suspension (i.e. as liquid antimicrobial products) for various pathogenic bacteria [Xie, Yanping; He, Yiping; Irwin, Peter L.; Jin, Tony; and Shi, Xianming; “Antimicrobial Activity and Mechanism of Action of Zinc Oxide Nanoparticles Against Camylobacter jejuni”, Applied and Environmental Microbiology 77(7), p 2325-2331, (2011); Yousef, Jehad M.; and Danial, Enas N.; “In Vitro Antibacterial Activity and Minimum Inhibitory Concentration of Zinc Oxide and Nano-particle Zinc Oxide Against Pathogenic Strains”, Journal of Health Sciences 2(4), p 38-42, (2012); Wang, Chao; Liu, Lian-Long; Zhang, Ai-Ting; Xie, Peng; Lu, Jian-Jun; and Zou, Ziao-Ting; “Antimicrobial Effects of Zinc Oxide Nanoparticles on Escherichia coli K88”, African Journal of Biotechnology 11(44), p 10248-10254, (2012)]. However, when these particles are “fixed” onto devices or surfaces such as coatings or composites, the level of antimicrobial performance is greatly diminished. There have been numerous attempts to incorporate ZnO into useful antimicrobial products, and even though antimicrobial effects are claimed, they are most often trivial. For instance, dental implants containing 10% ZnO nanoparticles showed only a 80% (<1 log) reduction of bacteria (Sevinc, Berdan, Aydin, and Hanley, Luke; “Antimicrobial Activity of Dental Composites Containing Zinc Oxide Nanoparticles”, Journal of Biomedical Materials Research, Part B, Applied Biomaterials 94(1), p 22-31 (2011). One study reported “significant” reductions of bacteria by incorporating ZnO nanoparticles into PVC composites; however, the actual measured reduction was less than 50%, even when the composites contained 75% ZnO (Seil, Justin T.; and Webster, Thomas J.; “Zinc Oxide Nanoparticle and Polymer Antimicrobial Biomaterial Composites”, MRS Proceedings 1316, (2010). Zinc oxide-filled UHMWPE composites showed only “slight inhibition” of Staph. aureus (Chang, B. P.; Akil, H. Md.; Nasir, R. Md.; and Nurdijati, S.; “Mechanical and Antimicrobial Properties of Treated and Untreated Zinc Oxide Filled UHMWPE Composites”, Journal of Thermoplastic Composite Materials 24(5), p 653-667, (2011). ZnO nanoparticles coated onto textile fabrics gave only a 97% reduction of Staph. aureus (SA), and 87% reduction of E. coli, prior to any laundering (Singh, Gagandeep; Joyce, Eadaoin M.; Beddow, James; and Mason, Timothy J.; “Evaluation of Antimicrobial Activity of ZnO Nanoparticles Coated Sonochemically onto Textile Fabrics”, Biotechnology and Food Sciences 2(1), p 106-120, (2012). A similar textile study found almost identical low reduction levels, and efficacy against EC dropped to just 40% after only one laundering (Rajendran, R.; Balakumar, C.; Ahammed, Hasabo A.; Mohammed, Jayakumar S.; Vaideki, K.; and Rajesh, E. M.; “Use of Zinc Oxide Nano Particles for Production of Antimicrobial Textiles”, International Journal of Engineering, Science and Technology 2(1), p 202-208, (2010). Silicon wafers coated with ZnO showed only a 10% reduction in 24-hour biofilm formation (Gittard, Shaun D.; Perfect, John R.; Montiero-Riviere, Nancy A; Wei, Wei; Jin, Chunming; and Narayan, Robert, J.; “Assessing the Antimicrobial Activity of Zinc Oxide Thin Films Using Disk Diffusion and Biofilm Reactor”, Applied Surface Science 255(11), p 5806-5811, (2009). The point here is that although ZnO, even in nanoparticulate form, is widely touted as having antimicrobial properties, it is relatively ineffective when incorporated into coatings or composites. The current invention will increase the antimicrobial efficacy of coatings containing ZnO by a few orders of magnitude (to at least the 3-log to 6-log level) via reacting the coatings with cleaning agents comprising HP.
The exact mechanism for the antimicrobial effect of ZnO is still somewhat of a mystery (Xie 2011, Zhang, Lingling; Jiang, Yunhong; Ding, Yulong; Daskalakis, Nikolaos; Jeuken, Lars; Povey, Malcolm; O′Neill, Alex J.; and York, David W.; “Mechanistic Investigation into Antimicrobial Behavior of Suspensions of ZnO Nanoparticles against E. coli”, Journal of Nanoparticle Research 12(5), p 1625-1636, (2010); however, it is widely known that ZnO can generate hydrogen peroxide and other reactive oxygen species upon exposure to UV light (Xie 2011, Wang 2012). There is also evidence that ZnO can interact with, and cause disruption of, the bacterial cell walls.
Zinc oxide and hydrogen peroxide are known to react with each other to form “zinc peroxide”. Zinc peroxide (ZP) is used as an oxidant, an antimicrobial, a blowing agent, and in the vulcanization of rubber, and its synthesis was patented in 1903 (U.S. Pat. No. 740,832). In 1951, Wood patented an improved method of producing zinc peroxide, which involved using sulfuric acid to essentially hydrolyze and “soften” the ZnO for improved yield (U.S. Pat. No. 2,563,442). Later, Dana (U.S. Pat. No. 4,172,841) found that a solution of zinc acetate mixed with HP was useful for producing antimicrobial textiles. This chemistry essentially amounted to an in-situ deposition of ZP on the textile fabric. Similar results were found using both zirconium and magnesium salts (U.S. Pat. Nos. 4,174,418 and 5,656,037). Reaction of zinc oxide and/or zinc hydroxide with HP has been used to synthesize nanoparticles of ZP (Rosenthal-Toib, Liora; Zohar, Keren; Alagem, Meital; and Tsur, Yoed; “Synthesis of Stabilized Nanoparticles of Zinc Peroxide”, Chemical Engineering Journal 136, p 425-429, (2008, Singh, Nahar; Mittal, Shelly; Sood, K. N.; Rashmi; and Gupta, Prabat K.; “Controlling the Flow of Nascent Oxygen Using Hydrogen Peroxide Results in Controlling the Synthesis of ZnO/ZnO2”, Chalcogenide Letters 7(4), p 275-281, (2010). Zinc hydroxide (ZH) is easily formed in solution by reaction of zinc salts with sodium hydroxide, but is difficult or impossible to isolate in the dry state due to conversion to ZnO as it dries. ZnO on the other hand, can also be hydrolyzed back to ZH, and either ZnO or ZH can react with HP to form ZP, which can undergo a slow hydrolysis releasing HP in the presence of water. In other words, the ZH/ZnO/HP/ZP system essentially involves the sequestration of HP in a reversible manner. This slow release of HP is responsible for observed antimicrobial effect of ZP-based materials. Herein lies the key element of the current invention—it is a sequestration system for storage (sequestration) and controlled release of antimicrobially-effective amounts of hydrogen peroxide.
Several major companies have recently introduced HP-based cleaning products. Lysol (Reckitt Benckiser) has come out with an entire product line of household cleaning products based on hydrogen peroxide: “Guided by our LYSOL® Mission for Health, we are proud to introduce the innovative LYSOL® Power & Free™ product line to consumers who are in search of trusted, powerful cleaning agents that help to maintain a healthy home by using the very common, yet very effective household staple of hydrogen peroxide,” (see http://www.prnewswire.com/news-releases/lysol-launches-line-of-hydrogen-peroxide-products-that-marks-a-new-era-in-household-cleaning-165569576.html). The label on Lysol's general purpose cleaner lists 0.9% HP as the active ingredient. Clorox has recently introduced a line of HP-based cleaners and wipes for hospital use—“Clorox Healthcare™ Hydrogen Peroxide Cleaner Disinfectants” (see http://www.cloroxprofessional.com/products/clorox-healthcare-hydrogen-peroxide-cleaner-disinfectants/at-a-glance/). The Clorox Material Safety Data Sheet lists “1 to 5%” as the concentration of HP.